Synthesis and bioactive evaluation of -((1-methyl-1-indol-3-yl)methyl)--(3,4,5-trimethoxyphenyl)acetamide derivatives as agents for inhibiting tubulin polymerization.

Based on the inhibitory effect of CA-4 analogues and indoles on tubulin polymerization, we designed and synthesized a series of -((1-methyl-1-indol-3-yl)methyl)-2-(1-pyrazol-1-yl or triazolyl)--(3,4,5-trimethoxyphenyl)acetamides. All the synthesized compounds were evaluated for their antiproliferative activities against HeLa, MCF-7 and HT-29 cancer cell lines, and some of the target compounds demonstrated effective activities towards the three tumour cell lines. Among them, compound 7d exhibited the most potent activities against HeLa (IC = 0.52 μM), MCF-7 (IC = 0.34 μM) and HT-29 (IC = 0.86 μM). Mechanistic studies revealed that compound 7d induced cell apoptosis in a dose-dependent manner, arrested the cells in the G2/M phase and inhibited polymerization of tubulin a consistent way with colchicine. Therefore, 7d is a potential agent for the further development of tubulin polymerization inhibitors.